1. Field of the Invention:
This invention relates to optionally substituted 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-N-(1H-tetrazol-5-yl)-carboxamide derivatives and to their use as inhibitors of allergic reactions.
2. Description of the Prior Art:
Various medicinal agents have been employed in the treatment of allergic reactions such as bronchial asthma and allergic rhinitis which are believed to result mainly from antigenantibody interaction. With respect to bronchial asthma, one of the most serious of these allergically-mediated diseases, bronchodilators such as theophylline, isoproterenol, epinephrine and atropine are used primarily in providing symptomatic relief. These agents, however, have undesirable side effects, e.g. cardiac stimulation and gastrointestinal distress.
With the recent introduction of disodium cromoglycate described by J. S. G. Cox, et al. in Adv. in Drug Res., 5, 115-196 (1970), the physician has been provided with an agent which, when administered to asthmatic patients prior to inhalation of specific antigens, inhibits the release of mediators, e.g. histamine and SRS-A (slow-reacting-substance of anaphylaxis), believed to be responsible for the asthmatic response. While making possible a prophylactic treatment for bronchial asthma without cardiovascular side effects and thus representing a significant advance, disodium cromoglycate suffers from a major disadvantage in that it is not orally absorbed and must be administered by inhalation.
With respect to the compounds of the present invention, no examples of 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-N-(1H-tetrazol-5-yl)carboxamides have been found in the literature. Numerous examples of 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylic acid derivatives are known, however. Illustrative of such compounds are the following:
1. Preparation of the unsubstituted acid and ester of the formula ##STR1## where R is hydrogen or ethyl is disclosed by S. Ruhemann in Ber., 30, 821 (1897). PA1 2. The p-methylphenyl and p-methoxyphenyl substituted esters and acids of the formula ##STR2## where R is hydrogen or ethyl and X is methyl or methoxy are disclosed by Mitter, et al. in J. Chem. Soc., 123, 2179 (1923) and Quart. J. Indian Chem. Soc., 2, 61 (1925). PA1 3. Shen, et al. in U.S. Pat. Nos. 3,660,403 and 3,745,161 disclose compounds of the general formula ##STR3## where R--Ar-- may inter alia be substituted phenyl, Y may be hydrogen and X is any of various substituents including hydroxy, alkoxy or N-heterocyclo. The reference compounds are disclosed as having antiinflammatory, antipyretic and analgesic activity, and no mention is made of any utility as antiallergy agents. PA1 4. U.S. Pat. No. 3,883,653 discloses antiallergy compounds of the formula ##STR4## PA1 5. U.S. Pat. No. 3,448,107 discloses lipid regulating agents of the formula ##STR5## where X.sup.1 and X.sup.2 may be various substituents including hydroxy, phenyl, p-chlorophenyl, p-methylphenyl and p-aminophenyl and n may be 0 to 4. PA1 6. U.S. Pat. No. 4,031,093 discloses 1,6-dihydro-6-oxo-2(ortho-substituted phenyl)pyrimidine-5-carboxylic acid derivatives of the formula ##STR6## wherein Z.sup.a is --O--C.sub.1 --C.sub.6 alkyl, --O--C.sub.2 --C.sub.6 alkenyl, --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 (CH.sub.2).sub.x O(CH.sub.2).sub.y CH.sub.3 in which x and y are each independently either 0 or an integer from 1 to 6, --OCF.sub.3, --OCH.sub.2 CF.sub.3, --O(CH.sub.2).sub.u CO.sub.2 R.sup.a in which u is an integer from 1 to 6 and R.sup.a is hydrogen or C.sub.1 -C.sub.6 alkyl, R.sup.c --COO-- in which R.sup.c is C.sub.1 -C.sub.6 alkyl, --O--CONHR.sup.b in which R.sup.b is C.sub.1 -C.sub.6 alkyl, --O(CH.sub.2).sub.k OH in which k is an integer from 2 to 6, ##STR7## Z.sup.b has the meaning stated above for Z.sup.a and in addition may be hydrogen, halogen, amino, C.sub.1 -C.sub.6 alkylamino, di(C.sub.1 -C.sub.6)-alkylamino, --N(CH.sub.2).sub.r in which r is 4 or 5, ##STR8## carb(C.sub.1 -C.sub.6)alkoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, CF.sub.3, hydroxy, C.sub.1 -C.sub.6 alkylthio, R.sup.c --CO-- in which R.sup.c is C.sub.1 -C.sub.6 alkyl or R.sup.c --CONH-- in which R.sup.c is C.sub.1 -C.sub.6 alkyl, Z.sup.c is hydrogen or C.sub.1 -C.sub.6 alkoxy and R is hydrogen or the residue of an easily cleavable ester group or a pharmaceutically acceptable salt thereof, provided that when Z.sup.a is methoxy, Z.sup.b and Z.sup.c are not hydrogen and when Z.sup.c is C.sub.1 -C.sub.6 alkoxy, Z.sup.a and Z.sup.b are both C.sub.1 -C.sub.6 alkoxy. PA1 7. U.S. Pat. No. 4,082,751 discloses 2-phenyl-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one derivatives of the formula ##STR9## wherein R.sup.1, R.sup.2 and R.sup.3 which may be the same or different are each hydrogen, halogen, (lower)alkyl, (lower)alkenyl, (lower)alkoxy, --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an integer from 2 to 7, --OCH.sub.2 (CH.sub.2).sub.x O(CH.sub.2).sub.y CH.sub.3 in which x is 0 or an integer from 1 to 6 and y is 0 or an integer from 1 to 6, CF.sub.3, --OCF.sub.3, --OCH.sub.2 CF.sub.3, hydroxy, (lower)alkylthio, amino, nitro, --N(CH.sub.2).sub.r in which r is 4 or 5, ##STR10## (lower)alkylamino, di(lower)alkylamino, carboxyl, --CO.sub.2 --(lower)alkyl, --O(CH.sub.2).sub.u CO.sub.2 R.sup.a in which u is an integer from 1 to 6 and R.sup.a is hydrogen or (lower)alkyl, acyl, acylamino, acyloxy, ##STR11## in which R.sup.b is (lower)alkyl, --O(CH.sub.2).sub.k OH in which k is an integer from 2 to 6, ##STR12## and pharmaceutically acceptable salts thereof, with the proviso that R.sup.1, R.sup.2 and R.sup.3 may not all be alike except in the case where they represent (lower)alkoxy. PA1 (a) Halogen includes chlorine, bromine, fluorine and iodine; PA1 (b) (Lower)alkyl includes both straight and branched chain saturated aliphatic hydrocarbon radicals having from 1-6 carbon atoms inclusive, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.; PA1 (c) (Lower)alkenyl includes straight or branched unsaturated aliphatic hydrocarbon radicals containing one double bond and having from 2-6 carbon atoms inclusive, e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl; PA1 (d) (Lower)alkoxy includes C.sub.1 -C.sub.6 alkoxy radicals, the alkyl portion of such radicals being defined as in (b) above. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, etc.; PA1 (e) --O--(Lower)alkenyl groups include radicals in which the alkenyl portion is as defined above in (c), e.g. vinyloxy, allyloxy or isopropenyloxy; PA1 (f) --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n includes cyclo(lower)-alkyloxy and cyclo(lower)alkyl-(C.sub.1 -C.sub.6)alkyloxy groups in which the cycloalkyl ring contains from 3 to 8 carbon atoms, preferably 3-6 carbon atoms. Examples of such groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, cyclobutylethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethyloxy and cyclohexylpropyloxy; PA1 (g) --O--CH.sub.2 (CH.sub.2).sub.x O(CH.sub.2).sub.y CH.sub.3 includes radicals such as --OCH.sub.2 OCH.sub.3, --OCH.sub.2 CH.sub.2 OCH.sub.3, --OCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3, --OCH.sub.2 OCH.sub.2 CH.sub.3 and --OCH.sub.2 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3 ; PA1 (h) (lower)alkylthio includes C.sub.1 -C.sub.6 alkylthio radicals in which the alkyl portion is as defined above in (b). Examples of such groups are methylthio, ethylthio, n-propylthio and n-butylthio; PA1 (i) (Lower)alkylamino includes C.sub.1 -C.sub.6 alkylamino radicals in which alkyl is as defined in (b). Examples of such groups as methylamino, ethylamino, propylamino and butylamino; PA1 (j) Di(lower)alkylamino includes di C.sub.1 -C.sub.6 alkylamino radicals in which alkyl is as defined above in (b). Examples of such groups are dimethylamino and diethylamino; PA1 (k) --CO--(Lower)alkyl includes ester radicals in which the alkyl moiety is as defined above in (b), e.g. carbomethoxy, carbethoxy, carbopropoxy and carbobutoxy; PA1 (l) --O(CH.sub.2).sub.u CO.sub.2 R.sup.a represents radicals such as --OCH.sub.2 CO.sub.2 H, --OCH.sub.2 CH.sub.2 CO.sub.2 H, --OCH.sub.2 CH.sub.2 CH.sub.2 CO.sub.2 H, --OCH.sub.2 CO.sub.2 CH.sub.3, --OCH.sub.2 CO.sub.2 C.sub.2 H.sub.5, --OCH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 and --OCH.sub.2 CH.sub.2 CO.sub.2 C.sub.2 H.sub.5 ; PA1 (m) --N(CH.sub.2)r includes pyrrolidino and piperidino; PA1 (n) ##STR16## includes (lower)alkyl carbamoyloxy radicals in which the (lower)alkyl portion is as defined above in (b). Examples of such substituents include --OCONHCH.sub.3, --OCONHC.sub.2 H.sub.5 and --OCONHC.sub.3 H.sub.7 ; and PA1 (o) --O--(Lower)alkynyl includes groups in which the alkynyl moiety is a straight or branched unsaturated aliphatic hydrocarbon radical containing one triple bond and having from 2 to 6 carbon atoms inclusive, e.g. ethynyloxy, propargyloxy, butynyloxy, pentynyloxy or hexynyloxy. PA1 (a) compounds where R.sup.1 is (lower)alkoxy, most preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy; PA1 (b) compounds where R.sup.1 is --O--(lower)alkenyl, most preferably allyloxy; PA1 (c) compounds where R.sup.1 is --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an integer from 2 to 7, most preferably cyclopropylmethoxy; and PA1 (d) compounds where R.sup.1 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, allyloxy or cyclopropylmethoxy and R.sup.2 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, allyloxy, cyclopropylmethoxy, amino or dimethylamino. PA1 (a) compounds where R.sup.1 is (lower)alkoxy, most preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy; PA1 (b) compounds where R.sup.1 is --O--(lower)alkenyl, most preferably allyloxy; PA1 (c) compounds where R.sup.1 is --O--(CH.sub.2).sub.m --CH(CH.sub.2).sub.n in which m is 0 or an integer from 1 to 6 and n is an integer from 2 to 7, most preferably cyclopropylmethoxy; PA1 (d) compounds where R.sup.1 is --O--(lower)alkynyl; and PA1 (e) compounds where R.sup.1 is --OCH.sub.2 C.sub.6 H.sub.5.
where m is an integer of 0 or 1 and Ar is pyridyl, thienyl, furyl, phenyl or phenyl substituted by hydroxy, methyl, methoxy, nitro, chloro, fluoro, 3,4-dimethoxy, 3,4,5-trimethoxy or alkanoylamino.